通过MAP激酶调节碳酸合成酶
L M Graves1, H I Guy, P Kozlowski
1Department of Pharmacology, Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 27599-7365, USA. lmg@med.unc.edu
Nature
|February 5, 2000
概括
线素激活蛋白 (MAP) 激酶信号调节CAD酶,对细胞生长至关重要. 这种调节通过减少反抑制和增加对激活剂的敏感性来增强皮里米丁合成,从而支持哺乳动物细胞增殖.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 细胞调节 细胞调节 细胞调节
背景情况:
- 新的皮里米丁核酸合成对于哺乳动物细胞增殖至关重要.
- 碳酸合成酶 (CPS II) 是该途径中的关键酶,是多功能CAD酶的一部分.
- 对CAD活动的调节对于控制皮里米丁生物合成至关重要.
研究的目的:
- 研究基因激活蛋白 (MAP) 激酶级联在调节多功能CAD酶中的作用.
- 阐明MAP酶介导酸化如何影响CAD的全调节及其对胺合成的影响.
主要方法:
- 在实验室中通过MAP激酶对CAD的酸化.
- 在哺乳动物细胞中使用表皮生长因子 (EGF) 刺激的体内研究.
- 对CAD全调节的分析 (反抑制和激活灵敏度).
- 在CAD上的共识MAP激酶酸化位点的突变.
- 测量细胞尿素三酸盐水平.
主要成果:
- 在体外对CAD的MAP激酶酸化和体内EGF刺激减少了尿素三酸盐的反抑制.
- 在MAP激酶激活后,CAD对基酸的激活变得更加敏感.
- 在体内,EGF诱导的CAD酸化与这些全变化有关.
- 抑制MAP激酶可以防止这些调节性转变.
- 关键酸化部位的突变取消了EGF刺激的全调节.
- EGF增加了细胞尿素三酸盐,这种效应通过MAP激酶抑制而逆转.
结论:
- 通过酸化,MAP激酶信号直接调节CAD活动.
- 这些调节性变化有利于通过调节CAD的全性质来促进细胞生长的pyrimidine生物合成.
- 这些发现确定了MAP激酶级联激活和控制de novo胺核酸合成之间的直接联系.
相关概念视频
01:02Phosphorylation
The addition or removal of phosphate groups from proteins is the most common chemical modification that regulates cellular processes. These modifications can affect the structure, activity, stability, and localization of proteins within cells as well as their interactions with other proteins.
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
02:54Protein Kinases and Phosphatases
Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
01:19Allosteric Proteins-ATCase
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
01:07MAPK Signaling Cascades
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
01:25cAMP-dependent Protein Kinase Pathways
Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
01:16Calmodulin-dependent Signaling
Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...